This invention relates to novel diarylalkyl cyclic diamine derivatives.
This invention also relates to chemokine receptor antagonists that may be effective as a therapeutic agent and/or preventive agent for diseases such as atherosclerosis, rheumatoid arthritis, psoriasis, asthma, ulcerative colitis, glomerulonephritis, multiple sclerosis, pulmonary fibrosis, and myocarditis, in which tissue infiltration of blood monocytes and lymphocytes plays a major role in the initiation, progression or maintenance of the disease.
Chemokines are a group of inflammatory/immunomodulatory polypeptide factors produced by lymphatic tissues and by activated macrophages and leukocytes at inflammatory sites; they have a molecular weight of 6-15 kD, contain four cysteine residues, are basic and have heparin binding activity. The chemokines can be classified into two subfamilies, the CXC chemokines and CC chemokines, by the common location of the four cysteine residues and by the differences in the chromosomal locations of the genes encoding them. For example IL-8 (abbreviation for interleukin-8 is a CXC chemokine, while the CC chemokines include MIP-1xcex1/xcex2 (abbreviation for macrophage inflammatory protein-1xcex1/xcex2), MCP-1 (abbreviation for monocyte chemotactic protein-1), and RANTES (abbreviation for regulated on activation, normal T-cell expressed and secreted cytokine). There also exists a chemokine called lymphotactin, which does not fall into either chemokine subfamily. These chemokines promote cell migration, increase the expression of cellular adhesion molecules such as integrins, and promote cellular adhesion, and are thought to be the protein factors intimately involved in the adhesion and infiltration of leukocytes into the pathogenic sites in such as inflammatory tissues (for references, see for example, Michiel, D., Biotechnology, 1993, 11, 739; Oppenheim, J. J., et al., Annual Review of Immuology, 1991, 9, 617-648; Schall, T. J., Cytokine, 1991, 3, 165-183; Springer, T. A., Cell, 1994, 76, 301-314; Furie, M. B., American Journal of Pathology, 1995, 146, 1287-1301; Kelner, G. S., et al.; Science, 1994, 266, 1395-1399).
For example, HIP-1xcex1 induces cell migration and causes a transient increase in intracellular calcium ion concentration levels, an increase in the expression of integrins, adhesion molecules, and degranulation of monocytes and lymphocytes, and inhibits bone marrow stem cell proliferation (See for example, Wolpe, S. D., et al., Journal of Experimental Medicine, 1998, 167, 570-581; Wolpe, S. D., et al., Faseb Journal, 1989, 3, 2565-2573; Taub, D. D., at al., Science, 1993, 260, 355-358; Schall. T. J., at al., Journal of Experimental Medicine, 1993, 177, 1821-1825; Neote, K., et al., Cell, 1993, 72, 415-425; Vaddi, K., et al., The Journal of Immunology, 1994, 153, 4721-4732).
With respect to the activity of HIP-1xcex1 in vivo and its role in the pathogenesis of disease, it has been reported that it is a pyrogen in rabbits (see for example Davatelis, G., et al., Science, 1989, 243, 1066-1068); that MIP-1xcex1 injection into mouse foot pads results in an inflammatory reaction such as infiltration by neutrophils and mononuclear cells (see for example Alam, R., et al., The Journal of Immunology, 1994, 152, 1298-1303); that MIP-1xcex1 neutralizing antibody has an inhibitory effect or a therapeutic affect in animal models of granuloma, multiple sclerosis and idiopathic pulmonary fibrosis (see for example Lukacs, N. W., et al., Journal of Experimental Medicine, 1993, 177, 1551-1559; Koprus, K. J., et al., The Journal of Immunology, 1995, 155, 5003-5010; Smith, R. E., et al., The Journal of Immunology, 1994, 153, 4704-4712); and that coxsackie virus induced myocarditis is inhibited in mice with a disrupted MIP-1xcex1 gene (see for example Cook, D. N. et al., Science, 1995, 269, 1583-1585). These studies indicate that MIP-1xcex1 is deeply involved in the local attraction of various subtypes of leukocytes and the initiation, progression and maintenance of resulting inflammatory response.
MCP-1 (also known as MCAF (abbreviation for macrophage chemotactic and activating factor) or JE) is a chemokine produced by macrophages, smooth muscle cells, fibroblasts, and vascular endothelial cells and causes cell migration and cell adhesion of monocytes, memory T cells, and natural killer cells, as well as mediating histamine release by basophils (For reference, see for example, Rollins, B. J., et al., Proc. Natl. Acad. Sci. USA, 1988, 85, 3738-3742; Matsushima, K., at al., Journal of Experimental Medicine, 1989, 169, 1485-14907; Yoshimura, T. et al., Febs Letters, 1989, 244, 487-493; Rollins, B. J. et al., Blood, 1991, 78, 1112-1116; Carr, M. W., at al., Proc. Natl. Acad. Sci. USA, 1994, 91, 3652-3656; Jiang, Y., et al., American Journal of Physiology, 1994, 267, C1112-C1118; Allavena, P., et al., European Journal of Immunology, 1994, 24, 3233-3236; Alam, R., et al., The Journal of Clinical Investigation, 1992, 89, 723-728).
In addition, high expression of MCP-1 has been reported in diseases where accumulation of monocyte/macrophage and/or T cells is thought to be important in the initiation or progression of diseases, such as atherosclerosis, restenosis due to endothelial injury following angioplasty, rheumatoid arthritis, glomerulonephritis, pulmonary fibrosis, asthma and psoriasis (for reference, see for example, Firestein, G. S. et al., Arthritis and Rheumatism, 1990, 33, 768-773; Nikolic-Peterson, D. J., et al., Kidney International, 1994, 45, enlarged ed., 45, S79-S82; Thomas, P. D., et al., American Review of Respiratory Disease, 1987, 135, 747-760; Ross, R., Nature, 1993, 362, 801-809; Cooper, K. D., et al., The Journal of Investigative Dermatology, 1994, 102, 128-137; Sousa, A. R., et al., American Journal of Respiratory Cell And Molecular Biology, 1994). Furthermore, anti-MCP-1 antibody has been reported to inhibit delayed type hypersensitivity and hepatitis (for reference, see for example Rand, M. L., et al., American Journal of Pathology, 1996, 148, 855-864; Wada, T., et al., Faseb Journal, 1996, 10, 1418-1425).
These data indicate that chemokines such as MIP-1xcex1 and MCP-1 attract monocytes and lymphocytes to disease sites and mediate their activation and thus are thought to be intimately involved in the initiation, progression and maintenance of diseases deeply involving monocytes and lymphocytes, such as atherosclerosis, rheumatoid arthritis, psoriasis, asthma, ulcerative colitis, glomerulonephritis, multiple sclerosis, pulmonary fibrosis and myocarditis.
Therefore, drugs which inhibit the action of chemokines on target cells may be effective as a therapeutic and/or preventive drug in diseases such as atherosclerosis, rheumatoid arthritis, psoriasis, asthma, ulcerative colitis, glomerulonephritis, multiple sclerosis, pulmonary fibrosis, and myocarditis.
Genes encoding receptors of specific chemokines have been cloned, and it is now known that these receptors are G protein-coupled seven-transmembrane receptors present on various leukocyte populations (for reference, see for example, Holmes, W. E., et al., Science 1991, 253, 1278-1280; Murphy P. M., et al., Science, 253, 1280-1283; Neote, K. et al., Cell, 1993, 72, 415-425; Charo, I. F., et al., Proc. Natl. Acad. Sci. USA, 1994, 91, 2752-2756; Yamagami, S., et al., Biochem. Biophys. Res. Commun., 1994, 202, 1156-1162; Combadier, C., et al., The Journal of Biological Chemistry, 1995, 270, 16491-16494, Power, C. A., et al., J. Biol. Chem., 1995, 270, 19495-19500; Samson, H., et al., Biochemistry, 1996, 35, 3362-3367; Murphy, P. M., Annual Review of Immunology, 1994, 12, 592-633). Therefore, compounds which inhibit the binding of chemokines such as MIP-1xcex1 and/or MCP-1 to these receptors, that is, chemokine receptor antagonists, may be useful as drugs which inhibit the action of chemokines such as MIP-1xcex1 and/or MCP-1 on the target cells, but there are no drugs known to have such effects.
Cyclic diamine derivatives containing diarylalkyl groups are known to have muscarine receptor antagonistic activity (JP09-020758, Kokai) and may be useful as a drug in the treatment of substance abuse disorders (WO9320821), may potentiate the effect of anti-cancer drugs by the inhibition of P-glycoproteins (JP03-101662, Kokai; EP363212), has calcium antagonistic activity ((a) DE3831993, (b) WO9013539, (c) JP63-280081, Kokai; EP289227, (d) JP62-167762, Kokai; DE3600390), have activity on the central nervous system and inhibits hypermotility (WO8807528), have antiaggression, antipsychotic, antidepressant and, analgesic effect (JP57-500828, Kokai), has coronary vasodilating activity (JP51-098281, Kokai), has anti-lipidemia effect and promotes vascular blood flow (JP49-093379, Kokai; EP42366), have coronary vasodilating activity and anti-reserpine activity (Aritomi, J., et al., Yakugaku Zasshi, 1971, 91, 972-979); have anti-serotonin and anti-histamine activity (JP45-031193, Kokoku); and have central nervous system depressant activity (Vadodaria, D. J., et al., J. Med. Chem., 1969, 12, 860-865). However, these compounds differ from the novel compounds of the present invention and these compounds have not been known to interfere with binding of chemokines to the target cells.
Therefore, it is an object of the present invention to discover small molecule drugs which inhibit the binding of chemokines such as MIP-1xcex1 and/or MCP-1 to their receptors on the target cells.
It is another object of the present invention to establish a method to inhibit the binding to the receptors on the target cells and/or effects on target cells of chemokines such as MIP-1xcex1 and/or MCP-1.
It is an additional object of the present invention to propose a method for the treatment of diseases for which the binding of chemokines such as MIP-1xcex1 and/or MCP-1 to the receptor on the target cell is one of the causes.
As a result of their intensive studies, the present inventors discovered that a cyclic diamine derivative having a diarylalkyl group or its pharmacologically acceptable acid adduct has an excellent activity to inhibit the binding of chemokines such as MIP-1xcex1 and/or MCP-1 and the like to the receptor of a target cell, which has led to the completion of this invention.
That is, the present invention provides a cyclic diamine derivative or its pharmacologically acceptable acid adduct (Invention 1), represented by the formula [I] below: 
[wherein R1 and R2 are identical to or different from each other representing a phenyl group or an aromatic heterocyclic group having 1-3 heteroatoms, selected from oxygen atoms, sulfur atoms, and/or nitrogen atoms, in which the phenyl or aromatic heterocyclic group may be substituted by any number of halogen atoms, hydroxy groups, C1-C8 lower alkyl groups, C1-C6 lower alkoxy groups, phenyl groups, benzyl groups, phenoxy groups, methylenedioxy groups, C1-C6 hydroxyalkyl groups, carboxy groups, C2-C7 alkoxycarbonyl groups, C2-C7 alkanoylamino groups, dioxolanyl groups, or by group represented by the formula: xe2x80x94NR5R6, or else may be condensed with a benzene ring to form a condensed ring, furthermore above substituents for the phenyl or aromatic heterocyclic group and the condensed ring condensed with a benzene ring are optionally substituted by any substituents independently selected from halogen atoms, hydroxy groups, or C1-C6 lower alkoxy groups, and R5 and R6 may be identical to or different from each other representing hydrogen atoms, C1-C6 lower alkyl groups , or C2-C6 lower alkenyl groups;
R3 represents a hydrogen atom, hydroxy group, cyano group, C1-C6 lower alkoxy group or C2-C7 lower alkanoyloxy group;
j represents an integer of 0-3;
k represents 2 or 3;
R4 is a group represented by:
Formula: xe2x80x94A1xe2x80x94R7xe2x80x83xe2x80x831)
(in the formula, R7 represents a phenyl group which may be substituted by any number of the same or different {halogen atoms, hyroxy groups, amino groups, C1-C6 lower alkyl groups, C1-C6 lower alkoxy groups, cyano groups, nitro groups, trifluoromethyl groups, C2-C7 alkoxycarbonyl groups, C2-C7 alkanoyl groups, C1-C6 alkylsulfonyl groups, trifluoromethylsulfonyl groups, phenylsulfonyl groups (which may be substituted with a hydroxy group}, 1-pyrrolylsulfonyl groups, C1-C6 hydroxyalkylsulfonyl groups, C1-C6 alkanoylamino groups, or a group represented by the formula: xe2x80x94CONR8R9) in which R8 and R9, identical to or different from each other, represent hydrogen atoms or C1-C6 lower alkyl groups; A1 is a group represented by the formula: xe2x80x94(CH2)mxe2x80x94 or a group represented by formula: xe2x80x94(CH2)pxe2x80x94Gxe2x80x94(CH2)qxe2x80x94 in which G represents G1 or G2; G1 represents xe2x80x94Oxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94COxe2x80x94Oxe2x80x94, xe2x80x94CONHxe2x80x94, xe2x80x94NHCOxe2x80x94, xe2x80x94NHCONHxe2x80x94, or xe2x80x94NHxe2x80x94SO2xe2x80x94; G2 represents xe2x80x94(Cxe2x95x90NH)NHxe2x80x94SO2xe2x80x94, xe2x80x94COxe2x80x94NHxe2x80x94NHxe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94NHxe2x80x94NHxe2x80x94COxe2x80x94NR10xe2x80x94, xe2x80x94COxe2x80x94NHxe2x80x94CH2xe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94NHxe2x80x94NHxe2x80x94SO2xe2x80x94, or xe2x80x94COxe2x80x94N(CH2xe2x80x94COxe2x80x94OCH3)xe2x80x94NHxe2x80x94COxe2x80x94; R10 represents a hydrogen atom or a phenyl group; m is an integer of 0-3; p is an integer of 1-3; q represents 0 or 1):
Formula: xe2x80x94A2xe2x80x94R11xe2x80x83xe2x80x832)
(wherein A2 represents xe2x80x94COxe2x80x94 or xe2x80x94SO2xe2x80x94; R11 represents:
a) A phenyl group which may be substituted by any number of the same or different (halogen atoms, C1-C6 lower alkyl groups, C1-C6 lower alkoxy groups, groups represented by formula xe2x80x94CH2xe2x80x94NR12R13 or groups represented by the formula: 
b) An aromatic monocyclic heterocyclic group having 1-3 heteroatoms, selected from oxygen atoms, sulfur atoms, and/or nitrogen atoms, and optionally substituted with any of the same or different number of (halogen atoms, C1-C6 lower alkyl groups, C1-C6 lower alkoxy groups), or
c) A group represented by the formula: xe2x80x94CH2xe2x80x94NR15R16,
where R12, R13, R14 and R15, identical or different groups, represent hydrogen atoms or C1-C6 lower alkyl groups and R16 represents (a phenyl group or a phenylalkyl group), which may be substituted by any number of the same or different halogen atoms, C1-C6 lower alkyl group, or C1-C6 lower alkoxy group);
Formula: xe2x80x94(CH2)nxe2x80x94R17xe2x80x83xe2x80x833)
(in the formula, R17 is a group which may be substituted at any possible sites by any number of the same or different (halogen atoms, hydroxy groups, C1-C6 lower alkyl groups, or C1-C6 lower alkoxy group s), representing
a hydrogen atom, cyano group, C2-C7 alkoxycarbonyl group, C1-C6 hydroxyalkyl group, C1-C6 lower alkynyl group, C3-C6 cycloalkyl group, C3-C7 alkenoyl group, a group represented by the formula: xe2x80x94(CHOH)CH2OR18, a group represented by the formula: xe2x80x94COxe2x80x94NHxe2x80x94NHxe2x80x94COxe2x80x94OR19, a group represented by the formula: 
a group represented by the formula: 
a group represented by the formula: 
a group represented by the formula: 
a group represented by the formula: 
a group represented by the formula: 
a group represented by the formula: 
a group represented by the formula: 
a group represented by the formula: 
a group represented by the formula: 
a group represented by the formula: 
in which n represents an integer of 1-4; R18 is C1-C6 lower alkyl group, C2-C6 lower alkenyl group, or C2-C6 lower alkynyl group and R19 represents a C1-C6 lower alkyl group);
Formula: xe2x80x94(CH2)rxe2x80x94A3xe2x80x94R20xe2x80x83xe2x80x834)
(wherein r represents an integer of 0-3; A3 represents a single bond, xe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94NHxe2x80x94NHxe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94NHxe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94, xe2x80x94COxe2x80x94NHxe2x80x94CH2xe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94NHxe2x80x94NHxe2x80x94SO2xe2x80x94, xe2x80x94(CHOH)xe2x80x94CH2xe2x80x94, or xe2x80x94(CHOH)xe2x80x94CH2OCH2xe2x80x94; R20 represents an aromatic heterocyclic group containing 1-3 heteroatoms, selected from oxygen atoms, sulfur atoms, and/or nitrogen atoms in which the aromatic heterocyclic group may be substituted by any number of the same or different (halogen atoms, C1-C6 lower alkyl groups, C1-C6 lower alkoxy groups, or pyrrolyl groups) or may be condensed with a benzene ring to form a condensed ring); or
Formula: xe2x80x94CH2xe2x80x94COxe2x80x94NR21R22xe2x80x83xe2x80x835)
(wherein R21 represents a hydrogen atom or C1-C6 lower alkyl group; R22 represents a hydrogen atom, C1-C6 lower alkyl group, a group represented by the formula: 
a group represented by the formula: 
or R21 and R22 may be taken together with the nitrogen to form a 4 to 7-membered saturated heterocycles, which may contain an oxygen atom, sulfur atom, or another nitrogen atom; where s represents 0 or 1; t represents an integer of 0-2; R23 represents a hydrogen atom, hydroxy group, phenyl group, C1-C6 lower alkyl group, or C1-C6 lower alkoxy group; R24 represents a hydrogen atom or phenyl group which may be substituted by hydroxy group; R25 represents a hydrogen atom, phenyl group (which may be substituted by hydroxy group), C2-C7 alkoxycarbonyl group, C1-C6 lower alkyl group, C1-C6 alkylthio group, or 3-indolyl group; and R26 represents a hydroxy group, amino group, C1-C6 lower alkoxy group, or phenylalkyloxy group);
Excepting that if R3 is a hydrogen atom, then, j is not 0, substituent for R7 is not hydroxy, C1-C6 lower alkyl or C1-C6 lower alkoxy; G1 is not xe2x80x94Oxe2x80x94 or xe2x80x94COxe2x80x94; its substituents, if R11 is a phenyl group, are not C1-C6 lower alkyl group; R17 is not a hydrogen atom, C2-C7 alkoxycarbonyl group, or C1-C6 hydroxyalkyl group; r is not 0 and A3 is not a single bond or xe2x80x94COxe2x80x94.
Furthermore, if R3 represents a hydrogen atom and k represents 2, R7 is not unsubstituted; m is not 0 and R11 is not a substituted or unsubstituted phenyl group.
If R3 is a cyano group, R7 is not unsubstituted, and the substituent groups for R7 are not halogen atom, C1-C6 lower alkyl group or C1-C6 lower alkoxy group.]
The present invention provides a method of inhibiting the binding of chemokines to the receptor of a target cell and/or a method to inhibit its action onto a target cell using a pharmacological formulation containing as an active ingredient, a cyclic diamine derivative or its pharmacologically acceptable acid adduct (Invention 2) represented by the formula [II] below: 
(wherein R1 and R2 are identical to or different from each other representing a phenyl group or an aromatic heterocyclic group having 1-3 heteroatoms, selected from oxygen atoms, sulfur atoms, and/or nitrogen atoms, in which the phenyl or aromatic heterocyclic group may be substituted by any number of halogen atoms, hydroxy groups, C1-C8 lower alkyl groups, C1-C6 lower alkoxy groups, phenyl groups, benzyl groups, phenoxy groups, methylenedioxy groups, C1-C6 hydroxyalkyl groups, carboxy groups, C2-C7 alkoxycarbonyl groups, C2-C7 alkanoylamino groups, dioxolanyl groups, or by group represented by the formula: xe2x80x94NR5R6, or else may be condensed with a benzene ring to form a condensed ring, furthermore above substituents for the phenyl or aromatic heterocyclic group and the condensed ring condensed with a benzene ring are optionally substituted by any substituents independently selected from halogen atoms, hydroxy groups, or C1-C6 lower alkoxy groups, and R5 and R6 may be identical to or different from each other representing hydrogen atoms, C1-C6 lower alkyl groups, or C2-C6 lower alkenyl groups;
R3 represents a hydrogen atom, hydroxy group, cyano group, C1-C6 lower alkoxy group or C2-C7 lower alkanoyloxy group;
j represents an integer of 0-3;
k represents 2 or 3;
R4 is a group represented by:
Formula: xe2x80x94A1xe2x80x94R7xe2x80x83xe2x80x831)
(in the formula, R7 represents a phenyl group which may be substituted by any number of the same or different {halogen atoms, hydroxy groups, amino groups, C1-C6 lower alkyl groups, C1-C6 lower alkoxy groups, cyano groups, nitro groups, trifluoromethyl groups, C2-C7 alkoxycarbonyl groups, C2-C7 alkanoyl groups, C1-C6 alkylsulfonyl groups, trifluoromethylsulfonyl groups, phenylsulfonyl groups (which may be substituted with a hydroxy group}, 1-pyrrolylsulfonyl groups, C1-C6 hydroxyalkylsulfonyl groups, C1-C6 alkanoylamino groups, or a group represented by the formula: xe2x80x94CONR8R9) in which R8 and R9, identical to or different from each other, represent hydrogen atoms or C1-C6 lower alkyl groups; A1 is a group represented by the formula: xe2x80x94(CH2)mxe2x80x94 or a group represented by formula: xe2x80x94(CH2)pxe2x80x94Gxe2x80x94(CH2)qxe2x80x94 in which G represents G1 or G2; G1 represents xe2x80x94Oxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94COxe2x80x94Oxe2x80x94, xe2x80x94CONHxe2x80x94, xe2x80x94NHCOxe2x80x94, xe2x80x94NHCONHxe2x80x94, or xe2x80x94NHxe2x80x94SO2xe2x80x94; G2 represents xe2x80x94(Cxe2x95x90NH)NHxe2x80x94SO2xe2x80x94, xe2x80x94COxe2x80x94NHxe2x80x94NHxe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94NHxe2x80x94NHxe2x80x94COxe2x80x94NR10xe2x80x94, xe2x80x94COxe2x80x94NHxe2x80x94CH2xe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94NHxe2x80x94NHxe2x80x94SO2xe2x80x94, or xe2x80x94COxe2x80x94N(CH2xe2x80x94COxe2x80x94OCH3)xe2x80x94NHxe2x80x94COxe2x80x94; R10 represents a hydrogen atom or a phenyl group; m is an integer of 0-3; p is an integer of 1-3; q represents 0 or 1):
Formula: xe2x80x94A2xe2x80x94R11xe2x80x83xe2x80x832)
(wherein A2 represents xe2x80x94COxe2x80x94 or xe2x80x94SO2xe2x80x94; R11 represents:
a) A phenyl group which may be substituted by any number of the same or different (halogen atoms, C1-C6 lower alkyl groups, C1-C6 lower alkoxy groups, groups represented by formula xe2x80x94CH2xe2x80x94NR12R13 or groups represented by the formula: 
b) An aromatic monocyclic heterocyclic group having 1-3 heteroatoms, selected from oxygen atoms, sulfur atoms, and/or nitrogen atoms, and optionally substituted with any of the same or different number of (halogen atoms, C1-C6 lower alkyl groups, C1-C6 lower alkoxy groups), or
c) A group represented by the formula: xe2x80x94CH2xe2x80x94NR15R16,
where R12, R13, R14 and R15, identical or different groups, represent hydrogen atoms or C1-C6 lower alkyl groups and R16 represents (a phenyl group or a phenylalkyl group), which may be substituted by any number of the same or different halogen atoms, C1-C6 lower alkyl group, or C1-C6 lower alkoxy group):
Formula: xe2x80x94(CH2)nxe2x80x94R17xe2x80x83xe2x80x833)
(in the formula, R17 is a group which may be substituted at any possible sites by any number of the same or different (halogen atoms, hydroxy groups, C1-C6 lower alkyl groups, or C1-C6 lower alkoxy groups), representing
a hydrogen atom, cyano group, C2-C7 alkoxycarbonyl group, C1-C6 hydroxyalkyl group, C1-C6 lower alkynyl group, C3-C6 cycloalkyl group, C3-C7 alkenoyl group, a group represented by the formula: xe2x80x94(CHOH)CH2OR18, a group represented by the formula: xe2x80x94COxe2x80x94NHxe2x80x94NHxe2x80x94COxe2x80x94OR19, a group represented by the formula: 
a group represented by the formula: 
a group represented by the formula: 
a group represented by the formula: 
a group represented by the formula: 
a group represented by the formula: 
a group represented by the formula: 
a group represented by the formula: 
a group represented by the formula: 
a group represented by the formula: 
a group represented by the formula: 
in which n represents an integer of 1-4; R18 is C1-C6 lower alkyl group, C2-C6 lower alkenyl group, or C2-C6 lower alkynyl group and R19 represents a C1-C6 lower alkyl group):
Formula: xe2x80x94(CH2)rxe2x80x94A3xe2x80x94R20xe2x80x83xe2x80x834)
(wherein r represents an integer of 0-3; A3 represents a single bond, xe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94NHxe2x80x94NHxe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94NHxe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94, xe2x80x94COxe2x80x94NHxe2x80x94CH2xe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94NHxe2x80x94NHxe2x80x94SO2xe2x80x94, xe2x80x94(CHOH)xe2x80x94CH2xe2x80x94, or xe2x80x94(CHOH)xe2x80x94CH2OCH2xe2x80x94; R20 represents an aromatic heterocyclic group containing 1-3 heteroatoms, selected from oxygen atoms, sulfur atoms, and/or nitrogen atoms in which the aromatic heterocyclic group may be substituted by any number of the same or different (halogen atoms, C1-C6 lower alkyl groups, C1-C6 lower alkoxy groups, or pyrrolyl groups) or may be condensed with a benzene ring to form a condensed ring):
Formula: xe2x80x94CH2xe2x80x94COxe2x80x94NR21R22xe2x80x83xe2x80x835)
(wherein R21 represents a hydrogen atom or C1-C6 lower alkyl group; R22 represents a hydrogen atom, C1-C6 lower alkyl group, a group represented by the formula: 
a group represented by the formula: 
or R21 and R22 may be taken together with the nitrogen to form a 4 to 7-membered saturated heterocycles, which may contain an oxygen atom, sulfur atom, or another nitrogen atom; where s represents 0 or 1; t represents an integer of 0-2; R23 represents a hydrogen atom, hydroxy group, phenyl group, C1-C6 lower alkyl group, or C1-C6 lower alkoxy group; R24 represents a hydrogen atom or phenyl group which may be substituted by hydroxy group; R25 represents a hydrogen atom, phenyl group (which may be substituted by hydroxy group), C2-C7 alkoxycarbonyl group, C1-C6 lower alkyl group, C1-C6 alkylthio group, or 3-indolyl group; and R26 represents a hydroxy group, amino group, C1-C6 lower alkoxy group, or phenyalkyloxy group):
A hydrogen atom, C1-C6 alkanoyl group, or C2-C7 alkoxycarbonyl group.]
Here, the compounds represented by the above formula [II] have activities to inhibit the binding of chemokines such as MIP-1xcex1 and/or MCP-1 and the like to the receptor of a target cell and activities to inhibit physiological activities of cells caused by chemokines such as MIP-1xcex1 and/or MCP-1 and the lie.
(1) On Invention 1
In the above formula [I], R1 and R2 are identical to or different from each other representing a phenyl group or an aromatic heterocyclic group having 1-3 heteroatoms, selected from oxygen atoms, sulfur atoms, and/or nitrogen atoms, in which the phenyl or aromatic heterocyclic group may be substituted by any number of halogen atoms, hydroxy groups, C1-C6 lower alkyl groups, C1-C6 lower alkoxy groups, phenyl groups, benzyl groups, phenoxy groups, methylenedioxy groups, C1-C6 hydroxyalkyl groups, carboxy groups, C2-C7 alkoxycarbonyl groups, C1-C6 alkanoylamino groups, dioxolanyl groups, or by group represented by the formula: xe2x80x94NR5R6, or else may be condensed with a benzene ring to form a condensed ring. Unsubstituted aromatic heterocyclic groups having 1-3 heteroatoms, selected from oxygen atoms, sulfur atoms, and/or nitrogen atoms are specifically, for example, thienyl, furyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrinidinyl, triazinyl, triazolyl, oxadiazolyl, thiadiazolyl group and the like, preferably including thienyl, furyl, pyrrolyl, and pyridyl groups.
The halogen atom as substituents for a phenyl group or an aromatic heterocyclic group in R1 and R2 include fluorine atoms, chlorine atoms, bromine atoms, iodine atoms, suitably including fluorine atoms and chlorine atoms. The C1-C8 lower alkyl groups mean C1-C8 straight-chain or branched alkyl groups such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, tert-pentyl, isohexyl, 2-methylpentyl, 1-ethylbutyl, and the like, suitably specifically including, methyl, ethyl, and isopropyl groups. The C1-C6 lower alkoxy groups mean groups consisting of C1-C6 part of the aforementioned C1-C8 lower alkyl groups and oxy groups, specifically, for example, methoxy group and ethoxy group. The C1-C6 hydroxyalkyl groups are groups in which C1-C6 part of the aforementioned C1-C8 lower alkyl groups are substituted at their any positions by a hydroxy group, preferably and specifically for example, hydroxymethyl group, 2-hydroxyethyl group, and the like. The C2-C7 alkoxycarbonyl groups mean the aforementioned C1-C6 lower alkoxy groups and carbonyl groups, preferably specifically for example, a methoxycarbonyl group and ethoxycarbonyl group. The C2-C7 lower alkanoylamino groups mean C2-C7 lower straight-chain or branched alkanoylamino groups such as acetylamino, propanoylamino, butanoylamino, pentanoylamino, hexanoylamino, heptanoylamino, isobutyrylamino, 3-methylbutanoylamino, 2-methylbutanoylamino, pivaloylamino, 4-methylpentanoylamino, 3,3-dimethylbutanoylamino, 5-methylhexanoylamino group, and the like, where the preferred and specific example includes an acetylamino group. Condensed rings obtained by condensation with a benzene ring mean a ring obtained by the condensation with a benzene ring of a phenyl group or an aromatic monocyclic heterocyclic ring having 1-3 heteroatoms, selected from oxygen atoms, sulfur atoms, and/or nitrogen atoms, at any possible sites, suitably and specifically for example, naphthyl, indolyl, benzofuranyl, benzothienyl, quinolyl group, indolyl group, benzimidazolyl group.
R5 and R6 represent each independently hydrogen atoms, C1-C6 lower alkyl groups, or C2-C6 lower alkenyl groups. The C1-C6 lower alkyl groups are the same as defined for the aforementioned C1-C6 part of the C1-C8 lower alkyl groups as substituents for a phenyl group or an aromatic heterocyclic group in R1 and R2, where the same examples can be given for the preferred specific examples. The C2-C6 lower alkenyl groups are for example, C2-C6 straight-chain or branched alkenyl groups such as vinyl, allyl, 2-butenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 4-methyl-3-pentenyl, and the like, where preferred specific examples include allyl, 2-butenyl, and 3-butenyl group.
Furthermore above substituents for the phenyl or aromatic heterocyclic group and the condensed ring condenced with a benzene ring in R1 and R2 are optionally substituted by any substituents independently selected from halogen atoms, hydroxy groups, or C1-C6 lower alkoxy groups. The halogen atoms and C1-C6 lower alkoxy groups are the same as defined for the aforementioned substituents for a phenyl group or an aromatic heterocyclic group in R1 and R2, and the same examples can be listed as preferred specific examples.
R1 in the above formula [I] represents a hydrogen atom, hydroxy group, cyano group, C1-C6 lower alkoxy group, or C2-C7 lower alkanoyloxy group. The C1-C6 lower alkoxy groups are the same as defined for the C1-C6 lower alkoxy groups in the aforementioned substituents for a phenyl group or an aromatic heterocyclic group in R1 and R2; where the same examples can be given for their preferred specific examples. The C2-C7 lower alkanoyloxy groups mean C2-C7 lower straight-chain or branched alkanoyloxy groups such as acetyloxy, propanoyloxy, butanoyloxy, pentanoyloxy, hexanoyloxy, heptanoyloxy, isobutyryloxy, 3-methylbutanoyloxy, 2-methylbutanoyloxy, pivaloyloxy, 4-methylpentanoyloxy, 3,3-dimethylbutanoyloxy, 5-methylhexanoyloxy group, and the like, where the preferred and specific example includes an acetyloxy group. Preferred specific examples for R3 include a hydrogen atom and hydroxy group.
In the above formula [I], j represents an integer of 0-3. If R3 represents a hydrogen atom, j is not 0. It is particularly preferred for j to be 2.
k in the above formula [I] represents 2 or 3; it is particularly preferred to use a homopiperazine derivative in which k is 3.
R4 in the above formula [I] represents a group represented by:
Formula: xe2x80x94A1xe2x80x94R7,xe2x80x83xe2x80x831)
Formula: xe2x80x94A2xe2x80x94R11,xe2x80x83xe2x80x832)
Formula: xe2x80x94(CH2)nxe2x80x94R17,xe2x80x83xe2x80x833)
Formula: xe2x80x94(CH2)rxe2x80x94A3xe2x80x94R20, orxe2x80x83xe2x80x834)
Formula: xe2x80x94(CH2)xe2x80x94COxe2x80x94NR21xe2x80x94R22.xe2x80x83xe2x80x835)
Here xe2x80x94COxe2x80x94 represents a carbonyl group. It is particularly preferred for R4 to be represented by formula 1): xe2x80x94A1xe2x80x94R7 or formula 4): xe2x80x94(CH2)rxe2x80x94A3R20.
R7 represents a phenyl group which may be substituted by any number of the same or different (halogen atoms, hydroxy groups, amino groups, C1-C6 lower alkyl groups, C1-C6 lower alkoxy groups, cyano groups, nitro groups, trifluoromethyl groups, C2-C7 alkoxycarbonyl groups, C2-C7 alkanoyl groups, C1-C6 alkylsulfonyl groups, trifluoromethylsulfonyl groups, phenylsulfonyl groups (which may be substituted with a hydroxy group), 1-pyrrolylsulfonyl groups, C1-C6 hydroxalkylsulfonyl groups, C1-C6 alkanoylamino groups, or a group represented by the formula: xe2x80x94CONR8R9). However, if R3 represents a hydrogen atom, the substituent for a phenyl in R7 is not a hydroxy, C1-C6 lower alkyl, or C1-C6 lower alkoxy; if R3 is a hydrogen atom and k=2, R7 is not an unsubstituted phenyl group; if R3 represents a cyano group, R7 is not unsubstituted and the substituent for a phenyl in R7 is not a halogen atom, C1-C6 lower alkyl, or C1-C6 lower alkoxy group.
The halogen atoms, C1-C6 lower alkyl groups, C1-C6 lower alkoxy groups, C2-C7 alkoxycarbonyl groups, and C2-C7 alkanoylamino groups as substituents for a phenyl in R7 are the same as defined for the aforementioned substituents for a phenyl group or an aromatic heterocyclic group in R1 and R2, and the same examples can be listed as preferred specific examples. The C2-C7 lower alkanoyl groups mean C2-C7 lower straight-chain or branched alkanoyl groups such as acetyl, propanoyl, butanoyl, pentanoyl, hexanoyl, heptanoyl, isobutyryl, 3-methylbutanoyl, 2-methylbutanoyl, pivaloyl, 4-methylpentanoyl, 3,3-dimethylbutanoyl, 5-methylhexanoyl group, and the like, where the preferred and specific example includes an acetyl group. The C1-C6 alkylsulfonyl groups mean those consisting of the aforementioned C1-C6 part of the C1-C6 lower alkyl groups and sulfonyl groups, preferably and specifically, for example, a methylsulfonyl group. The phenylsulfonyl groups may be substituted with a hydroxy group at any position. The C1-C6 hydroxyalkylsulfonyl groups mean those consisting of the aforementioned C1-C6 hydroxyallyl groups and sulfonyl groups, preferably and specifically, for example, a (2-hydroxyethyl) sulfonyl group. R8 and R9, the same or different groups, represent hydrogen atoms or C1-C6 lower alkyl groups. The C1-C6 lower alkyl groups as R8 and R9 are the same as defined for the aforementioned C1-C6 part of the C1-C8 lower alkyl groups as substituents for a phenyl group or an aromatic heterocyclic group in R1 and R2, and the same examples are listed for their preferred specific examples.
A1 is a group represented by the formula: xe2x80x94(CH2)mxe2x80x94 or a group represented by formula: xe2x80x94(CH2)pxe2x80x94Gxe2x80x94(CH2)qxe2x80x94 in which G represents G1 or G2; G1 represents xe2x80x94Oxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94COxe2x80x94Oxe2x80x94, xe2x80x94CONHxe2x80x94, xe2x80x94NHCOxe2x80x94, xe2x80x94NHCONHxe2x80x94, or xe2x80x94NHxe2x80x94SO2xe2x80x94; G2 represents xe2x80x94(Cxe2x95x90NH)NHxe2x80x94SO2xe2x80x94, xe2x80x94COxe2x80x94NHxe2x80x94NHxe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94NHxe2x80x94NHxe2x80x94COxe2x80x94NR10xe2x80x94, xe2x80x94COxe2x80x94NHxe2x80x94CH2xe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94NHxe2x80x94NHxe2x80x94SO2xe2x80x94, or xe2x80x94COxe2x80x94N(CH2xe2x80x94COxe2x80x94OCH3)xe2x80x94NHxe2x80x94COxe2x80x94; R10 represents a hydrogen atom or a phenyl group; m is an integer of 0-3; p is an integer of 1-3; q represents 0 or 1); however, if R3 is a hydrogen atom, G1 is not xe2x80x94Oxe2x80x94 or xe2x80x94COxe2x80x94; if R3 represents a hydrogen atom and if k=2, m is not 0. In the above formula, xe2x80x94COxe2x80x94 means a carbonyl group and xe2x80x94SO2xe2x80x94 means a sulfonyl group. Preferred A1 groups are specifically, for example, those represented by the formula xe2x80x94(CH2)mxe2x80x94, with m being preferably 1. Preferred A1 groups are also specifically, for example, xe2x80x94(CH2)pxe2x80x94COxe2x80x94NHxe2x80x94NHxe2x80x94COxe2x80x94(CH2)qxe2x80x94, xe2x80x94(CH2)pxe2x80x94COxe2x80x94NHxe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94(CH2)qxe2x80x94; xe2x80x94(CH2)pxe2x80x94COxe2x80x94NHxe2x80x94CH2xe2x80x94COxe2x80x94(CH2)qxe2x80x94; with p being preferably 1.
A2 represents xe2x80x94COxe2x80x94 (carbonyl group ) or xe2x80x94SO2xe2x80x94 (sulfonyl group).
R11 represents:
a) A phenyl group which may be substituted by any number of the same or different (halogen atoms, C1-C6 lower alkyl groups, C1-C6 lower alkoxy groups, groups represented by formula xe2x80x94CH2xe2x80x94NR12R13 or groups represented by the formula: 
b) An aromatic monocyclic heterocyclic group having 1-3 heteroatoms, selected from oxygen atoms, sulfur atoms, and/or nitrogen atoms, and optionally substituted with any of the same or different number of (halogen atoms, C1-C6 lower alkyl groups, C1-C6 lower alkoxy groups), or
c) A group represented by the formula: xe2x80x94CH2xe2x80x94NR15R16.
However if R3 represents a hydrogen atom, the substituent group for a phenyl group in R11 is not a C1-C6 lower alkoxy group; if R3 represents a hydrogen atom and k is 2, R11 is not a substituted or unsubstituted phenyl group. The halogen atoms, C1-C6 lower alkyl groups, or C1-C6 lower alkoxy groups as substituents for the groups in R11 are the same as defined for the aforementioned substituents for a phenyl group or an aromatic heterocyclic group in R1 and R2, and the same examples can be given as preferred specific examples.
Specific examples for R11 in which the aromatic monocyclic heterocyclic group is unsubstituted can be the same specific examples for the aromatic heterocyclic groups with no substituents in R1 and R2. Preferred examples specifically include a pyridyl group.
R12, R13, R14 and R15 represent each independently hydrogen atoms or C1-C6 lower alkyl groups. The C1-C6 lower alkyl groups are of the same definition for the aforementioned C1-C6 part of the C1-C8 lower alkyl groups as substituents for a phenyl group or an aromatic heterocyclic group in R1 and R2, where the same examples can be listed as preferred specific examples.
R16 represents a (phenyl group or phenylalkyl group) which may be substituted by any number of the same or different (halogen atoms, C1-C6 lower alkyl groups, or C1-C6 lower alkoxy group). The halogen atom, C1-C6 lower alkyl group or C1-C6 lower alkoxy group as substituents are the same as defined for the aforementioned substituents for a phenyl group or an aromatic heterocyclic group in R1 and R2, where the same examples can be given as preferred specific examples. The phenylalkyl group means a group consisting of a phenyl group and a C1-C6 alkylene group, preferably and specifically for example, a benzyl group.
R17 is a group which may be substituted at any possible sites by any number of the same or different (halogen atoms, hydroxy groups, C1-C6 lower alkyl groups, or C1-C6 lower alkoxy groups), representing
a hydrogen atom, cyano group, C2-C7 alkoxycarbonyl group, C1-C6 hydroxyalkyl group, C1-C6 lower alkynyl group, C3-C6 cycloalkyl group, C2-C7 alkenoyl group, a group represented by the formula: xe2x80x94(CHOH)CH2OR18, a group represented by the formula: xe2x80x94COxe2x80x94NHxe2x80x94NHxe2x80x94COxe2x80x94OR19, a group represented by the formula: 
a group represented by the formula: 
a group represented by the formula: 
a group represented by the formula: 
a group represented by the formula: 
a group represented by the formula: 
a group represented by the formula: 
a group represented by the formula: 
a group represented by the formula: 
a group represented by the formula: 
a group represented by the formula: 
If, however, R3 represents a hydrogen atom, R17 is not a hydrogen atom, C2-C7 alkoxycarbonyl group, or C1-C6 hydroxyalkyl group. R17 may be bonded at any possible site to an alkylene group xe2x80x94(CH2)nxe2x80x94. The C2-C7 alkoxycarbonyl and C1-C6 hydroxyalkyl groups are the same as defined for the aforementioned substituents for a phenyl group or an aromatic heterocyclic group in R1 and R2, where the same examples may be given as preferred specific examples. The C1-C6 lower alkynyl group means a C2-C6 straight-chain or branched alkynyl groups such as ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 3-butynyl, 4-pentynyl, 5-hexynyl, 1-methyl-4-pentynyl group, and the like, preferably and specifically, for example, ethynyl group and 1-propynyl group. The C3-C6 cycloalkyl groups mean cyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl groups and the like. The C3-C7 lower alkenoyl group means a C3-C7 straight-chain or branched alkenoyl groups such as propenoyl, 2-metylpropenoyl, 2-buenoyl, 3-butenoyl, 2-methyl-3-butenoyl, 3-methyl-2-butenoyl, 2-pentenoyl, 4-pentenoyl, 2-methyl-2-pentenoyl, 2,2-dimethyl-4-pentenoyl, 2-hexenoyl, 3-hexenoyl, 6-heptenoyl, and the like, preferably and specifically, for example propenoyl and 2-metylpropenoyl group.
The halogen atom, C1-C6 lower alkyl group or C1-C6 lower alkoxy groups as substituents for R17 are the same as defined for the aforementioned substituents for a phenyl group or an aromatic heterocyclic group in R1 and R2, and the same examples can be given as preferred specific examples.
R18 represents a C1-C6 lower allkyl group, C2-C6 lower alkenyl group, or C2-C6 lower alkynyl group. The C1-C6 lower alkyl groups are the same as defined for the aforementioned C1-C6 part of the C1-C6 lower alkyl groups as substituents for a phenyl group or an aromatic heterocyclic group in R1 and R2, where the same examples can be given as preferred specific examples. The C2-C6 lower alkenyl groups are the same as the C2-C6 lower alkenyl groups in the aforementioned R5 and R6, where the preferred examples are specifically allyl, 2-butenyl, and 3-butenyl group. The C2-C6 lower alkynyl groups are the same as the C2-C6 lower alkynyl groups in the aforementioned R17 where the preferred examples are specifically 2-propynyl group and 3-butynyl group.
R19 represents a C1-C6 lower alkyl group. Here, the C1-C6 lower alkyl group is the same as defined for the aforementioned C1-C6 part of the C1-C6 lower alkyl groups as substituents for a phenyl group or an aromatic heterocyclic group in R1 and R2, where the same examples can be given as preferred specific examples.
n is an integer of 1-4. It is particularly preferred for the n to be 1 or 2.
A3 represents a single bond, xe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94NHxe2x80x94NHxe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94NHxe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94, xe2x80x94COxe2x80x94NHxe2x80x94CH2xe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94NHxe2x80x94NHxe2x80x94SO2xe2x80x94, xe2x80x94(CHOH)xe2x80x94CH2xe2x80x94, or xe2x80x94(CHOH)xe2x80x94CH2OCH2xe2x80x94. However, if R3 represents a hydrogen atom. A3 is not a single bond. Here, xe2x80x94COxe2x80x94 means a carbonyl group and xe2x80x94SO2xe2x80x94 means a sulfonyl group. A3 is preferably a single bond or xe2x80x94COxe2x80x94NHxe2x80x94NHxe2x80x94COxe2x80x94.
R20 represents an aromatic heterocyclic group containing 1-3 heteroatoms, selected from oxygen atoms, sulfur atoms, and/or nitrogen atoms in which the aromatic heterocyclic group may be substituted by any number of the same or different (halogen atoms, C1-C6 lower alkyl groups, C1-C6 lower alkoxy groups, or pyrrolyl groups) or may be condensed with a benzene ring to form a condensed ring. As to specific examples in which the aromatic monocyclic heterocyclic group R20 has no substitution, the same specific example can be given as in the cases with no substituents on the aromatic heterocyclic rings in R1 and R2; preferred examples are specifically a pyridyl group and is oxazolyl group.
The halogen atom, C1-C6 lower alkyl group, or C1-C6 lower alkoxy group as substituents for the aromatic heterocyclic group in R20 are the same as defined for the aforementioned substituents for a phenyl group or an aromatic heterocyclic group in R1 and R2, where the same examples can be given as suitable specific examples. The condensed ring obtained by condensation with a benzene ring in R20 is the same as defined for the condenced ring in R1 and R2, where the same examples can be given as suitable specific examples.
r is an integer of 0-3. However, if R3 represents a hydrogen atom, r is not 0. In particular, it is preferred for r to be 1.
R21 represents a hydrogen atom or C1-C6 lower alkyl group. R22 represents a hydrogen atom, C1-C6 lower alkyl group, a group represented by the formula: 
a group represented by the formula: 
or may be taken together with the nitrogen to form a 4 to 7-membered saturated heterocycles, which may contain an oxygen atom, sulfur atom, or another nitrogen atom. The C1-C6 lower alkyl groups in R21 and R22 are the same as defined for the aforementioned C1-C6 part of the C1-C8 lower alkyl groups as substituents for a phenyl group or an aromatic heterocyclic group in R1 and R2, where the same examples can be given for the preferred specific examples. Saturated heterocyclic rings consisting of R21, R22, and the nitrogen include azetidine, pyrrolidine, piperidine, perhydroazepine, morpholine, thiamorpholine, piperazine, homopiperazine, and the like; preferred specific examples include piperidine, morpholine, and thiamorpholine.
s represents 0 or 1 and t represents an integer of 0-2.
R23 represents a hydrogen atom, hydroxy group, phenyl group, C1-C6 lower alkyl group, or C1-C6 lower alkoxy group. The C1-C6 lower alkyl group and C1-C6 lower alkoxy groups as R23 are the same as defined for the aforementioned substituents for a phenyl group or an aromatic heterocyclic group in R1 and R2, where the same examples can be given for the preferred specific examples.
R24 represents a hydrogen atom or phenyl group, where the phenyl group may be substituted by hydroxy group at any position.
R25 represents a hydrogen atom, phenyl group. C2-C7 alkoxycarbonyl group, C1-C6 lower alkyl group, C1-C6 alkylthio group, or 3-indolyl group, where the phenyl group may be substituted by hydroxy group at any position. The C2-C7 alkoxycarbonyl group and C1-C6 lower alkyl group as R25 are the same as defined for the aforementioned substituents for a phenyl group or an aromatic heterocyclic group in R1 and R2, where the same examples can be given for the preferred specific examples. The C1-C6 alkylthio group as R25 means a group consisting of thio group and C1-C6 part of the aforementioned C1-C8 lower alkyl groups for substituent in R1 and R2, specifically, for example, methylthio group and ethylthio group.
R26 represents a hydroxy group, amino group, C1-C6 lower alkoxy group, or phenylalkyloxy group. The C1-C6 lower alkoxy group is the same as defined for the aforementioned C1-C6 lower alkoxy group as substituent for a phenyl group or an aromatic heterocyclic group in R1 and R2, where the same examples can be given for the preferred specific examples. The phenylalkyl group means a group consisting of a phenyl group, a C1-C6 alkylene group, and a oxy group, preferably and specifically for example, a benzyl oxy group.
(2) On Invention 2
R1, R2, R3, j, and k in the above formula [II] are as the same as defined in the respective terms for the above formula [I] and the same examples can be listed for their preferred specific examples. R4 in the above formula [II] includes R4 defined in the respective terms for the above formula [I], where the same examples can be listed for their preferred specific examples, and furthermore R4 in the above formula [II] represents a hydrogen atom, C1-C6 alkanoyl group, or C2-C7 alkoxycarbonyl group. However, the above formula [II] does not involve the same limitations as made in the above formula [I] with respect to cases where R3 represents a hydrogen atom, where R3 represents a hydrogen atom and k represents 2, and where R3 represents cyano group.
The cyclic diamine derivative represented by the formula [II] above or its pharmacologically acceptable acid adduct can be used to prepare a chemokine receptor antagonist preparation of the present invention by formulating the therapeutically required amount and a carrier and/or diluent into a pharmaceutical composition. Thus, the cyclic diamine derivative shown by the above formula [II] or its pharmacologically acceptable acid adduct can be administered orally or by parenterally, for example, intravenously, subcutaneously, intramuscularly, percutaneously or intrarectally.
The oral administration can be accomplished in the form of tablets, pills, granules, powder, solution, suspension, capsules, etc.
The tablets for example can be prepared using a vehicle such as lactose, starch and crystallized cellulose; binder such as carboxymethylcellulose, methylcellulose, and polyvinylpyrrolidone; disintegrator such as sodium alginate, sodium bicarbonate and sodium lauryl sulfate, etc.
Pills, powder and granule preparations can be prepared by a standard method using the vehicles mentioned above. Solution or suspension can be prepared by a standard method using glycerin ester such as tricaprylin and triacetin or alcohols such as ethanol. Capsules can be made by charging granules, powder or solution in gelatin, etc.
Subcutaneous, intramuscular or intravenous preparations can be prepared as an injection using aqueous or nonaqueous solution. Aqueous solution for example may include isotonic sodium chloride solution. Nonaqueous solutions may include for example, propyleneglycol, polyethyleneglycol, olive oil, ethyl oleate, etc., and optionally, one can add antiseptics and stabilizers. For injection, one can be sterilized by filtration through a bacterial filter or combination of disinfectant.
Percutaneous administration may be in the form of an ointment or cream, and ointment can be prepared in the standard manner using fatty oils such as castor oil and olive oil. or Vaseline, while creams can be made using fatty oils or emulsifying agent such as diethylene glycol and sorbitan esters of fatty acid.
For intrarectal administration, one can use standard suppositories using gelatin soft capsules, etc.
The cyclic diamine derivative of the present invention or its pharmacologically acceptable acid adduct is administered at a dose that varies depending on the type of disease, route of administration, age and sex of patient, and severity of disease, but is likely to be 1-500 mg/day in an average adult.
(3) Matter Common Throughout Invention 1 and Invention 2
Preferred specific examples for the cyclic diamine derivatives in the above formula [I] or formula [II] include compounds having each substituent as shown in the following Tables 1.1-1.25.
The present invention can also use acid adducts of the cyclic diamine derivatives where such acids include, for example, mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, carbonic acid, and the like, as well as organic acids such as citric acid, malic acid, tartaric acid, fumaric acid, methanesulfonic acid, trifluoroacetic acid, and the like.
The present invention may use racemates and all possible optically active forms of the cyclic diamine derivatives represented by the above formula [I] or [II].
Compounds represented by the above general formula [I] and/or [II] can be synthesized by any of the general preparations given below.
(Preparation 1)
A preparation which call for treating one equivalent of a cyclic diamine derivative represented by the formula [III] below: 
[where R1, R2, R3, j, and k are as defined respectively in the above formula [I] or [II]] with 0.1-10 equivalents of a compound represented by the formula [IV] below:
X1xe2x80x94R4xe2x80x83xe2x80x83[IV]
[wherein R4 is the same as defined for the R4 in the above formula [I] or [II]; X1 is a halogen atom, alkylsulfonyloxy group, or arylsulfonyloxy group. R4 is not a group represented by the formula: xe2x80x94A2xe2x80x94R11 in where A2 and R11 are the same as defined respectively in the above formula [I] or [II]], either in absence or presence of solvent;
alternatively treating 1 equivalent of a cyclic diamine given by the formula [V] below: 
[where R4 and k are the same as defined respectively in the above formula [I] or [II]], with 0.1-10 equivalents of a compound represented by the formula [VI] below: 
[where R1, R2, R3, and j are the same as defined respectively in the above formula [I] or [II]; X1 represents a halogen atom, alkylsulfonyloxy, or arylsulfonyloxy group] either in the absence or presence of solvent.
Such reactions can be more smoothly run if a base is present. The base which may be used includes inorganic salts such as potassium carbonate, sodium carbonate, sodium hydrogencarbonate, and the like, or amines such as triethylamine, diisopropylethylamine, and pyridine, and the like. In addition, the reactions in these preparations can also be promoted by iodide such as potassium iodide, sodium iodide, or the like.
X1 in the above formulas [IV] and [VI] represents a halogen atom, alkylsulfonyloxy, or arylsulfonyloxy group. Such halogen atoms include preferably chlorine, bromine, and iodine atoms. Suitable specific examples for the alkylsulfonyloxy groups include methylsulfonyloxy and trifluoromethylsulfonyloxy group and the like. A preferred specific example for the arylsulfonyloxy group includes a tosyloxy group.
(Preparation 2)
A preparation which calls for treating 1 equivalent of a cyclic diamine derivative represented by the above formula [III] with 0.1-10 equivalents of a carboxylic acid, sulfonic acid represented by the formula [VII] below:
HOxe2x80x94A2xe2x80x94R11xe2x80x83xe2x80x83[VII]
[where R11 and A3 are the same as defined respectively in the above formulas [I] or [II]], or its reactive derivative, either in the absence or presence of solvent.
The reactive derivatives for the carboxylic acids or sulfonic acids in the above formula [VII] include highly reactive carboxylic or sulfonic acid derivatives, which are usually used in synthetic organic chemistry, such as acid halides, acid anhydrides, mixed acid anhydrides. If esters are used, the reaction can be run smoothly by activating the cyclic diamine derivative represented by the above general formula [III], for example, by using triethylaluminum.
Such reactions can be more smoothly run by using suitable amounts of a dehydrating agent such as molecular sieve, condensing agents such as dicyclohexyl carbodiimide, N-ethyl-Nxe2x80x2-(3-dimethylaminopropyl)carbodiimide, carbonyldiimidazole, and the like, or bases similar to those used in the above preparation 1.
(Preparation 3)
A preparation which calls for treating 1 equivalent of a cyclic diamine represented by the above formula [III], with 0.1-10 equivalents of an aldehyde represented by the formula [VIII] below:
R27xe2x80x94(CH2)zxe2x80x94CHOxe2x80x83xe2x80x83[VIII]
[where in the formula R17 represents either R7, R17, or R20 of the above formula [I] or [II]; z represents an integer of 0-3], either in the absence or the presence of solvent under reductive conditions, or else treating 1 equivalent of a compound represented by the above formula [V] with 0.1-10 equivalents of an aldehyde represented by the formula [IX] below: 
[where in the formula R1, R2, R3, and j are the same as defined respectively in the above formulais [I] or [II]], either in the absence or the presence of solvent under reductive conditions.
Such reactions are in general called reductive amination reactions and such reductive conditions may be generated by catalytic hydrogenation using a catalyst containing a metal such as palladium, platinum, nickel, rhodium, or the like, using complex hydrides such as lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, and the like, boranes, or electrolytic reduction, and the like.
(Preparation 4)
A preparation which calls for treating 1 equivalent of a cyclic diamine derivative represented by the formula [X] below: 
[where in the formula j, k, and R4 are the same as defined respectively for the above formula [I] or [II] and R28 represents a C1-C6 lower alkyl group] or 1 equivalent of a cyclic diamine derivative represented by the formula [XI] below: 
[where R1, j, k, and R4 are the same as defined respectively for the above formula [I] or [II]], with 0.1-10 equivalents of an organometallic reagent represented by the formula [XII] below:
R29xe2x80x94Mxe2x80x83xe2x80x83[XII]
[wherein the formula R29 is the same as defined for the R1 and R2 in the above formula [I] or [II]; M is a metal atom or its halide or complex] in the presence of solvent.
The organometallic reagents used in such preparations may be those suitably selected organometallic reagents known to cause a nucleophilic reaction toward esters and/or ketones in general in synthetic organic chemistry, such as Grignard reagents (M=MgX2), organolithium reagents (M=Li), organocerium reagents (M=CeX22,) (X2 represents a halogen atom). These organometallic reagents may be prepared by known methods from the corresponding halides. The halides preferably include chlorides, bromides, iodides.
If the substrates submitted to each of the above preparations contains a substituent which reacts under each reaction condition in general in synthetic organic chemistry or is thought to adversely affect the reaction, that functional group can be protected by a known suitable protecting group followed by the reaction of the above preparations and deprotection using a known procedure to ado obtain the desired compound.
Each of the above preparations may use solvents for the reaction such as halogenated hydrocarbons such as dichloromethane, chloroform, or the like, aromatic hydrocarbons such as benzene, toluene, and the like, ethers such as diethyl ether, tetrahydrofuran, or the like, esters such as ethyl acetate, aprotic polar solvents such as dimethylformamide, dimethyl sulfoxide, acetonitrile, and the like, alcohols such as methanol, ethanol, isopropyl alcohol, and the like.
The reaction temperature in either of the preparations should be in the range of xe2x88x9278-+150xc2x0 C., preferably 0xc2x0 C.-100xc2x0 C. After completion of the reaction, the usual isolation and purification operations such as concentration, extraction, recrystallization, chromatography, and the like may be used, to isolate the desired cyclic diamine derivatives represented by the above formula [I] or [II]. These can be converted into pharmacologically acceptable acid adducts by the usual method.
The chemokine receptor antagonist, which contain the cyclic diamine derivative or its pharmacologically acceptable acid adducts of this invention, which inhibits chemokines such as MIP-1xcex1 and/or MCP-1 and the like from action on target cells, are useful as therapeutic agents and/or preventive preparation for diseases such as atherosclerosis, rheumatic arthritis, psoriasis, asthma, ulcerative colitis, glomerulonephritis, multiple sclerosis, pulmonary fibrosis, myocarditis, and the like, in which tissue infiltration of blood monocytes, lymphocytes, and the like plays a major role in the initiation, progression, and maintenance of the disease.